Chiral Nitrones Research Articles

Synthesis of Nitrones and Nitroalkanes via Chiral Cyclic Imines.

A series of structurally chiral cyclic imines efficiently yields chiral nitrones and nitroalkanes. This is the first report of the synthesis of nitro groups by C═N bond cleavage of imines through a nitrone intermediate.

Enhanced synthesis of novel multisubstituted isoxazolidines as potential antimicrobial and antioxidant agents using zinc (II) catalyst, and in silico studies

In the effort of our endeavour to synthesize new heterocyclic bioactive agents, we succeed the synthesis of a new series of Multisubstituted isoxazolidines (3-(4- substituted)-5-(1H-imidazol-1-yl)-2-methyl-1,2-oxazolidine derivatives (3a–l) by 1,3-dipolar cycloaddition between chiral nitrone (1a–l) and 1-vinylimidazole. The spectral data was utilized to verify and elucidate the structures and mechanistic routes of all the products. By utilizing zinc chloride as a catalyst, the reaction rate was significantly enhanced, resulting in a reduction of the reaction time by over 100-fold. After the synthesis process, our objective was to examine the effectiveness of the synthesized compounds as antimicrobial agents against a range of bacterial and fungal species. The antimicrobial properties of the compounds were assessed using the macro double broth dilution method. with some exhibiting higher potency than established antibiotics and antifungals. Additionally, the compounds exhibited good antioxidant activity by in vitro assay, with 3c, 3g, and 3l showing higher activity than ascorbic acid. The study also evaluated the drug-likeness of the synthesized compounds and found that they followed Lipinski's rule of five, making them suitable for oral drug development. Molecular docking studies further supported the in vitro antibacterial evaluation The synthesized compounds demonstrated an excellent binding mode with the target 1QFG protein, some outperformed a standard drug.

Green and efficient synthesis of chiral amines and hydroxylamines by indium (zinc)-copper-mediated alkylation reaction in aqueous media

A simple and environmentally friendly method for the alkylation of various chiral nitrones in water using unactivated alkyl halides has been developed. Both the chiral amines and hydroxylamines could be obtained with superior yields and high diastereoselectivity, with a wise choice of different metal complexes. The novelly developed reaction has the characteristics of environmental protection, simple operating, high efficiency, and regioselectivity superbly.

Broadening the reaction scope of unprotected aldoses via their corresponding nitrones: 1,3-dipolar cycloadditions with alkenes.

Condensation reactions of unprotected tetroses and pentoses with hydroxylamines afforded nitrones, which were easily converted to densely functionalized isoxazolidines in the presence of electron-poor alkenes. The 1,3-dipolar cycloaddition occurred with good facial discrimination of the chiral nitrone but under rather low endo/exo control. Stereochemistry of isomers was ascertained by chemical correlation with known derivatives from the literature. Microwave activation appeared as the most efficient reaction mode, affording the expected adducts within several minutes whereas hours were needed under standard heating. Alternatively, the transformation proved also possible under high pressure conditions by using a hand pump system, avoiding any energy source. Although water could not be used as the solvent, leading to hydrolysis of the nitrone substrate, a large variety of organic solvents proved efficient. The method has potential use in the preparation of non-ionic carbohydrate-based amphiphiles.

Asymmetric [3+2] cycloaddition reaction of a chiral cyclic nitrone for the synthesis of new tropane alkaloids

The 1,3-dipolar cycloaddition of a chiral nitrone with α,β-unsaturated lactones was carried out to give the corresponding isoxazolidines. Tetrahydro-1,3-oxazines with an oxa-tropane skeleton were obtained in one step by alkylation. The structures of several of these compounds were corroborated by X-ray diffraction and molecular modelling studies confirmed the results and proposed a mechanism for their formation.

Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

AbstractAn approach to cyclic nitrones from N‐hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N‐OSEM [SEM=2‐(trimethylsilyl)ethoxymethyl] lactam forms a five‐membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one‐pot process. When combined with the N‐oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio‐pure form, enabling the concise total synthesis of cylindricine C.

Approach to Fully Substituted Cyclic Nitrones from N-Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C.

An approach to cyclic nitrones from N-hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N-OSEM [SEM=2-(trimethylsilyl)ethoxymethyl] lactam forms a five-membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one-pot process. When combined with the N-oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio-pure form, enabling the concise total synthesis of cylindricine C.

Total Synthesis of Neodysiherbaine A via 1,3-Dipolar Cycloaddition of a Chiral Nitrone Template.

The total synthesis of neodysiherbaine A was achieved via 1,3-dipolar cycloaddition of a chiral nitrone template with a sugar-derived allyl alcohol in the presence of MgBr2·OEt2. This cycloaddition constructed the C2 and C4 asymmetric centers in a single step. Then reductive cleavage, intramolecular SN2 reaction of the tertiary alcohol, and oxidation of the primary alcohol afforded neodysiherbaine A.

Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime.

We report realization of the first enantioselective Cope-type hydroamination of oximes for asymmetric nitrone synthesis. The ligand promoted asymmetric cyclopropene "hydronitronylation" process employs a Cu-based catalytic system and readily available starting materials, operates under mild conditions and displays broad scope and exceptionally high enantio- and diastereocontrol. Preliminary mechanistic studies corroborate a CuI-catalytic profile featuring an olefin metalla-retro-Cope aminocupration process as the key C-N bond forming event. This conceptually novel reactivity enables the first example of highly enantioselective catalytic nitrone formation process and will likely spur further developments that may significantly expedite chiral nitrone synthesis.

Stereoselective synthesis of enantiopure N-substituted pyrrolidin-2,5-dione derivatives by 1,3-dipolar cycloaddition and assessment of their in vitro antioxidant and antibacterial activities

1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.

1,4]-sigmatropic rearrangement of chiral nitrones and their utilization in the synthesis of new iminosugars.

Reflection on the epimerization of the α-stereocenter of sugar nitrones leads to the conclusion that the process may occur through [1,4]-sigmatropic rearrangement. Participation of an ionic mechanism was excluded by a deuterium labeling experiment, and DFT calculations showed a reasonable energy barrier for the proposed [1,4]-shift. Products of the intramolecular 1,3-dipolar cycloaddition of the studied nitrones were utilized in the diversity-oriented synthesis of polyhydroxy derivatives of piperidine, indolizidine and quinolizidine. Minimal activity against the screened glucosidases and human melanoma cell lines was observed for some of the obtained compounds.

Unexpected synthesis of aziridines under Cu(I) catalyzed Kinugasa conditions assisted by microwave irradiation

Cu(I)-catalyzed 1,3-dipolar cycloaddition between chiral nitrone and terminal alkynes under microwave irradiation afforded a series of enantiopure aziridines with the creation of two contiguous stereogenic centers.

Diastereoselective synthesis of β-lactams via Kinugasa reaction of acyclic chiral nitrones

An approach to β-lactams via a Kinugasa reaction between chiral copper acetylides and chiral acyclic nitrones bearing either 1,3-dioxane or 1,3-dioxolane moieties is reported. The stereochemical preferences observed in these reactions are discussed. The reaction provides access to a variety of interesting β-lactam structures. Electronic circular dichroism in combination with NMR spectroscopy was shown to be a useful and effective method for the reliable determination of the absolute configuration of all components of a complex mixtures of azetidinones. The effectiveness of the chiral analysis of complex mixtures was demonstrated for HPLC coupled on-line with electronic circular dichroism detection as well.

ChemInform Abstract: Stereoselective Nucleophilic Addition of PhSCF2SiMe3 to Chiral Cyclic Nitrones: Asymmetric Synthesis of gem‐Difluoromethylenated Polyhydroxypyrrolizidines and ‐indolizidines.

AbstractThe title compounds are obtained by a general method involving the sequential stereoselective fluoride‐catalyzed nucleophilic addition of PhSCF2SiMe3 as gem‐difluoromethylene building block to easily available chiral nitrones followed by reductive cleavage of the hydroxy group, N‐alkylation of the obtained pyrrolidines, intramolecular radical cyclization, and hydrogenolysis of the protecting group.

Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by “pH cycles” to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided...

ChemInform Abstract: Synthesis and Inhibition Study of Bicyclic Iminosugar‐Based Alkaloids, Scaffolds, and Libraries Towards Glucosidase.

AbstractA flexible synthetic route is presented for the preparation of various bicyclic iminosugar‐based alkaloids starting from the chiral nitrone (I).

ChemInform Abstract: Unprotected Xylose‐Derived Nitrone in Stereodivergent Synthesis of 4‐Hydroxypiperidine Enantiomers: Weak Lewis Acid Induced Alteration of Stereochemistry in 1,3‐Dipolar Cycloaddition.

AbstractThe two‐step synthesis of chiral bicyclic products (III) and (IV) involves the conversion of substrate (I) into the corresponding hydroxylamine followed by in situ formation of a chiral nitrone and intramolecular 1,3‐dipolar cycloaddition.

ChemInform Abstract: Diastereoselective Synthesis of Propargylic N‐Hydroxylamines via NHC—Copper(I) Halide‐Catalyzed Reaction of Terminal Alkynes with Chiral Nitrones on Water.

AbstractThe methodology is applied as key step in the synthesis of (‐)‐lentiginosine (XV).

Inside Back Cover: Stereoselective Nucleophilic Addition of PhSCF2SiMe3 to Chiral Cyclic Nitrones: Asymmetric Synthesis of gem‐Difluoromethylenated Polyhydroxypyrrolizidines and ‐indolizidines (Chem. Asian J. 4/2015)

Inside Back Cover: Stereoselective Nucleophilic Addition of PhSCF₂SiMe₃ to Chiral Cyclic Nitrones: Asymmetric Synthesis of <i>gem</i>‐Difluoromethylenated Polyhydroxypyrrolizidines and ‐indolizidines (Chem. Asian J. 4/2015)

ChemInform Abstract: Stereoselective Synthesis of Enantiopure Cycloalkylglycines by 1,3‐Dipolar Cycloaddition of a Chiral Nitrone to Cycloalkenes.

AbstractCyclic analogs of 4‐hydroxyisoleucine are synthesized in three simple steps from the methone‐based chiral nitrone (I).